In Industry Insights, members of ASPET’s Industry Science Committee discuss the intersection of pharmacology and industry, private sector highlights, and how the industry and membership can support each other.
The Intricacies of Developing Therapeutics Targeting G Protein-Coupled Receptors
By Alix Rouault, PhD
G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that mediate signaling through G proteins and β-arrestins. They are major targets in modern drug discovery, with more than 30% of approved therapeutics acting on GPCRs. Many receptors display subtle structural modifications that allow them to adapt their signaling inputs. The melanocortin system illustrates this diversity, comprising five distinct receptors (MC1-5R). The high receptor homology complicates selective drug design, as closely related receptors have evolved in some cases to respond to the same ligand. In addition, some GPCRs form heterodimers with single-transmembrane accessory proteins, such as melanocortin receptor accessory proteins 1 and 2 (MRAPs). MRAP2 has also been shown to interact with non-melanocortin GPCRs, including the ghrelin receptor (GHSR1a). Extensive studies demonstrate that MRAP2 heterodimerization stabilizes GHSR1a in an inactive conformation, markedly reducing basal G protein–mediated cAMP production. While unbound GHSR1a exhibits balanced ghrelin-induced signaling, MRAP2-bound GHSR1a shows reduced β-arrestin recruitment and enhanced G-protein activity. This mechanism enables tissues to fine-tune ligand responses according to their proteomic environment.
While the orthosteric pocket of a GPCR is the preferred matrix of endogenous peptides, such as ghrelin is for GHSR1a or α-MSH is for MC4R, allosteric pockets can be occupied by smaller peptides or molecules. Various compounds interface differently with their pockets. The pull ensuing from the compound interactions changes the tertiary or quaternary structure of receptors. Some conformations will change the affinity of the receptor for its G proteins and/or β-arrestins. Consequentially, the phenotypic response can also be modified. Therefore, both proteome and circulatory environment will determine the effect of a ligand.
Synthetic compounds are being developed to directly activate receptors or allosterically tune their conformations, thereby modulating endogenous signaling to control specific phenotypic responses. This next generation of precision medicines is expected to substantially reduce side effects. Early examples such as tirzepatide, developed by Eli Lilly, exhibit preferential activity at GLP-1R and GIPR while sparing GCGR. Similarly, the orally available agent xanomeline, designed by Bristol Myers Squibb, selectively targets the M1 and M4 muscarinic receptors.
The membrane expression of GPCRs can also be a critical determinant of signaling output and can strongly influence a compound’s pharmacological profile. Variations in receptor expression across tissues can lead to markedly different responses to the same compound, an effect that is far from benign and was elegantly described by Dr. Terry Kenakin, recipient of this year’s FASPET Award. The comparison of oxymetazoline and norepinephrine in tissues with variable adrenergic receptor expression illustrates the importance of reporting results as ∆log(Emax/EC50) in cross-system analyses. While changes in receptor density had little impact on norepinephrine’s potency and efficacy, oxymetazoline responses were highly sensitive to receptor expression levels. In tissues with high receptor expression, both ligands produced comparable responses; however, in lower-expression systems, norepinephrine activity remained largely unchanged, whereas oxymetazoline effect was markedly reduced. This differential sensitivity can enable selective targeting of high-expression tissues while sparing those with lower receptor levels.
GPCR drug discovery is a highly competitive sector. Industry leaders from the field will address some of these fascinating topics at ASPET 2026 in Minneapolis. The Industry Science Committee (ISC) is introducing a session titled, “Accelerating Biopharmaceutical Drug Discovery: Strategies and Scientific Frontiers,” which will showcase experts such as Dr. Ajay Yekkirala, Chief Scientific Officer at Superluminal Medicine, who will share advances on their Melanocortin program, and Dr. Jim Trevaskis, Associate Vice President in the Diabetes, Obesity and Complications Early Discovery Research Group at Eli Lilly, who will talk about a program he led targeting the Amylin receptors (the name given to the calcitonin receptor heterodimerized with different RAMP accessory proteins). Aspiring and seasoned researchers are invited to attend this session on May 18th from 1:00 pm to 2:30 pm.
